In the present study, we evaluated genotype distribution of TERT rs2853669 polymorphism and the frequency of somatic mutations in TERT promoter and in exon 3 of CTNNB1 gene in a series of HCV- and HBV-positive cases diagnosed with HCC or CC/HCC-CC, along with autologous non-tumor tissue, from people living in Southern Italy, a geographic area with a very high incidence of liver cancer. Here, CTNNB1 is linked to cholangiocarcinoma.